Regulation of Erythroid Differentiation via the HIF1α-NFIL3-PIM1 Signaling Axis Under Hypoxia.

Aims: Erythropoiesis is controlled by several factors, including oxygen level under different circumstances. However, the role of hypoxia in erythroid differentiation and the underlying mechanisms are poorly understood. We studied the effect and mechanism of hypoxia on erythroid differentiation of K562 cells and observed the effect of hypoxia on early erythropoiesis of zebrafish. Results: Compared with normal oxygen culture, both hemin-induced erythroid differentiation of K562 cells and the early erythropoiesis of zebrafish were inhibited under hypoxic treatment conditions. Hypoxia-inducible factor 1 alpha (HIF1α) plays a major role in the response to hypoxia. Here, we obtained a stable HIF1α knockout K562 cell line using the CRISPR-Cas9 technology and further demonstrated that HIF1α knockout promoted hemin-induced erythroid differentiation of K562 cells under hypoxia. We demonstrated an HIF1-mediated induction of the nuclear factor interleukin-3 (NFIL3) regulated in K562 cells under hypoxia. Interestingly, a gradual decrease in NFIL3 expression was detected during erythroid differentiation of erythropoietin-induced CD34+ hematopoietic stem/progenitor cells (HSPCs) and hemin-induced K562 cells. Notably, erythroid differentiation was inhibited by enforced expression of NFIL3 under normoxia and was promoted by the knockdown of NFIL3 under hypoxia in hemin-treated K562 cells. In addition, a target of NFIL3, pim-1 proto-oncogene, serine/threonine kinase (PIM1), was obtained by RNA microarray after NFIL3 knockdown. PIM1 can rescue the inhibitory effect of NFIL3 on hemin-induced erythroid differentiation of K562 cells. Innovation and Conclusion: Our findings demonstrate that the HIF1α-NFIL3-PIM1 signaling axis plays an important role in erythroid differentiation under hypoxia. These results will provide useful clues for preventing the damage of acute hypoxia to erythropoiesis.

NT-proBNP in Different Patient Groups of COPD: A Systematic Review and Meta-Analysis.

Purpose: NT-proBNP, a peptide biomarker synthesized and secreted by cardiomyocytes in response to cardiac load, has gained attention in recent years for its potential role in respiratory diseases. Chronic Obstructive Pulmonary Disease (COPD), a chronic and progressive inflammatory condition affecting the respiratory system, is frequently associated with comorbidities involving the cardiovascular system. Consequently, the aim of this systematic review and meta-analysis was to evaluate the variations in NT-proBNP levels across distinct patient groups with COPD and establish a foundation for future investigations into the precise clinical significance of NT-proBNP in COPD. Methods: The search databases for this study were conducted in PubMed, Excerpt Medica database (Embase), Web of Science (WOS), and Cochrane Library databases. Databases were searched for studies on the predictive value of NT-proBNP in adult COPD patients. Results: A total of 29 studies (8534 participants) were included. Patients with stable COPD exhibit elevated levels of NT-proBNP [standardized mean difference(SMD) [95CI%]=0.51 [0.13,0.89]; p=0.0092]. COPD patients with predicted forced expiratory volume in 1 s (FEV1) < 50% exhibit significantly elevated levels of NT-proBNP compared to those with FEV1 ⩾50%[SMD [95CI%]=0.17 [0.05,0.29]; p=0.0058]. NT-proBNP levels were significantly higher in acute exacerbations (AECOPD) compared to patients with stable COPD [SMD [95CI%]=1.18 [0.07,2.29]; p=0.037]. NT-proBNP levels was significantly higher in non-survivors than in survivors of hospitalised AECOPD patients [SMD [95CI%]=1.67 [0.47,2.88]; p=0.0063]. Both COPD patients with pulmonary hypertension(PH) [SMD [95CI%]=0.82 [0.69,0.96]; p<0.0001] and chronic heart failure(CHF) [SMD [95CI%]=1.49 [0.96,2.01]; p<0.0001] showed higher NT-proBNP level. Conclusion: NT-proBNP, a biomarker commonly used in clinical practice to evaluate cardiovascular disease, demonstrates significant variations in different stages of COPD and during the progression of the disease. The fluctuations in NT-proBNP levels could be indicative of the severity of pulmonary hypoxia and inflammation and cardiovascular stress among COPD patients. Therefore, assessing NT-proBNP levels in COPD patients can aid in making informed clinical decisions.

Efficacy and safety of three species of Rhodiola L. in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic hypoxia, inflammation, oxidative stress, and irreversible airflow limitations. Rhodiola L. is a genus of botanical drugs used in traditional medicine that may influence COPD. Objective: A systematic review of the safety and efficacy of Rhodiola L. in patients with COPD. Material and methods: We searched the PubMed, Embase, Cochrane Library, Web of Science, Scopus, China National Knowledge Infrastructure (CNKI), Chongqing VIP, Wanfang, and SinoMed databases. The search strategy used terms including "COPD" and "Rhodiola." Two independent reviewers conducted the literature screening, data extraction, and risk of bias assessment, with a third reviewer involved to resolve disagreements. Statistical analysis was conducted in Review Manager (version 5.4.1), following the Cochrane Handbook. Results: This review included nine studies, of which two focused on Rhodiola crenulata (Hook.f. and Thomson) H. Ohba (R. crenulata) and two on Rhodiola kirilowii (Regel) Maxim (R. kirilowii); the remaining five focused on Rhodiola wallichiana (Hook.) S.H.Fu (R. wallichiana). Compared with the placebo, patients who received Rhodiola L. presented no more adverse events (p = 0.65) but showed significant improvement in the percentage of forced expiratory volume in 1 s at prediction (FEV1%pred), forced expiratory volume in 1 s (FEV1), the ratio of forced expiratory volume in 1 s on forced vital capacity (FEV1/FVC), saturation of oxygen in arterial blood, partial pressure of oxygen in arterial blood (PaO2), partial pressure of carbon dioxide in arterial blood (PaCO2), systolic pulmonary arterial pressure, diastolic pulmonary arterial pressure, COPD assessment test, efficient rate, C-reactive protein, and N-terminal pro-B-type natriuretic peptide (all p < 0.01). Compared with ambroxol, R. kirilowii provided additional benefits to patients with COPD in FEV1%pred, FEV1, FEV1/FVC, PaO2, PaCO2, 8-iso-prostaglandin F2α, superoxide dismutase, glutathione, malondialdehyde, and total antioxidant capacity (all p < 0.01). Conclusion: Among the Rhodiola L. genus, this review included R. wallichiana, R. crenulata, and R. kirilowii, which might be safe and effective in COPD. Although this study has several limitations, further RCTs are needed. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=302881], identifier [CRD42022361890].

The role of B3GNT3 as an oncogene in the growth, invasion and migration of esophageal cancer cells.

PURPOSE: To investigate the role and mechanism of ß1,3-N-acetylglucosaminyltransferase-3 gene (B3GNT3) in esophageal cancer (ESCA). METHODS: The starBase database was used to evaluate the expression of B3GNT3. B3GNT3 function was measured using KYSE-30 and KYSE-410 cells of esophageal squamous cell carcinoma (ESCC) cell lines. The mRNA levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8, clone formation assay and transwell assay were used to detect the changes of proliferation, invasion and migration. RESULTS: B3GNT3 expression was higher in ESCA tissues than in normal tissues. The overall survival rate of ESCA patients with high B3GNT3 expression was lower than that of ESCA patients with low B3GNT3 expression. In vitro functional experiments showed that the proliferation ability, migration and invasion ability of KYSE-30 and KYSE-410 cells with B3GNT3 interference were lower than those of the control, and the overexpression of B3GNT3 had the opposite effect. After silencing B3GNT3 expression in ESCC cell lines, the growth of both cell lines was inhibited and the invasiveness was decreased. Knockdown of B3GNT3 reduced the growth rate and Ki-67 expression level. CONCLUSIONS: B3GNT3, as an oncogene, may promote the growth, invasion and migration of ESCC cell.

A systematic review and Bayesian meta-analysis of the antibiotic treatment courses in AECOPD.

Background: No consensus exists on the antibiotic treatment course for patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Former studies indicate that shorter courses might have the same efficacy with fewer adverse events, which is inconsistent with guidelines and general practice. Existing evidence allows us to conduct a systematic review and Bayesian analysis on this topic. Methods: Four databases were searched from their inception to January 5, 2023. All statistical estimations were performed using R. "Gemtc" was the core package of analysis. CINeMA was used to assess the grade of confidence of the results. Results: Fourteen studies were included in the Bayesian meta-analysis. No difference in the clinical success rate of antibiotic treatment was observed from a super short course (1-3 days) to a long course (≥10 days). Considering the adverse events, the short course (4-6 days) might be the safest. The majority of results were of high or moderate confidence grade. Conclusion: Short course might cause the fewest adverse events. The clinical efficacy of antibiotics might not depend on the course length. Undeniably, more systematic explorations are warranted to investigate the clinical application of a shorter course of antibiotic treatment.

The role of B3GNT3 as an oncogene in the growth, invasion and migration of esophageal cancer cells

Purpose: To investigate the role and mechanism of ß1,3-N-acetylglucosaminyltransferase-3 gene (B3GNT3) in esophageal cancer (ESCA). Methods: The starBase database was used to evaluate the expression of B3GNT3. B3GNT3 function was measured using KYSE-30 and KYSE-410 cells of esophageal squamous cell carcinoma (ESCC) cell lines. The mRNA levels were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8, clone formation assay and transwell assay were used to detect the changes of proliferation, invasion and migration. Results: B3GNT3 expression was higher in ESCA tissues than in normal tissues. The overall survival rate of ESCA patients with high B3GNT3 expression was lower than that of ESCA patients with low B3GNT3 expression. In vitro functional experiments showed that the proliferation ability, migration and invasion ability of KYSE-30 and KYSE-410 cells with B3GNT3 interference were lower than those of the control, and the overexpression of B3GNT3 had the opposite effect. After silencing B3GNT3 expression in ESCC cell lines, the growth of both cell lines was inhibited and the invasiveness was decreased. Knockdown of B3GNT3 reduced the growth rate and Ki-67 expression level. Conclusion: B3GNT3, as an oncogene, may promote the growth, invasion and migration of ESCC cell.

Comparative effectiveness of interventional therapeutic modalities for unresectable hepatocellular carcinoma: A systematic review and network meta-analysis.

It is unclear whether hepatic artery infusion chemotherapy (HAIC) or transcatheter arterial chemoembolization (TACE) is more efficient in the combination therapy of hepatocellular carcinoma (HCC). Head-to-head comparisons among HAIC-related therapies are lacking. For this network meta-analysis, PubMed, EMBASE and Cochrane Library databases were searched up to April 1, 2022. Randomized controlled trials (RCTs) were eligible if they evaluated the use or prolongation of TACE or HAIC in patients with advanced HCC and reported or collected survival data. A network meta-analysis was performed to synthesize data and make direct and indirect comparisons between treatments. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to explore the efficacy of various treatment options on overall survival (OS), odds ratios (ORs) with 95% CI were used for overall response rate (ORR), whereas risk ratios (RRs) with 95% CI were used for serious adverse events (SAEs). The analysis of 7 trials including a total of 1,073 patients found that sorafenib with HAIC-oxaliplatin improved survival (HR=0.33, 95% CI: 0.25-0.44); the ORR was also improved in patients treated with sorafenib plus HAIC-oxaliplatin and sorafenib plus PF-HAIC (OR=22.18, 95% CI: 10.69-52.56; and OR=2.72, 95% CI: 1.43-5.36, respectively). The incidence of liver injury was elevated in patients treated with sorafenib plus TACE (OR=5.93, 95% CI: 2.70-15.41). However, no differences in the incidences of other SAEs were identified among the treatment groups. The present meta-analysis provides preliminary evidence for the comparative safety and efficacy of HAIC and TACE combined with sorafenib, and indicates the dominance of HAIC-oxaliplatin in HCC interventional therapy. However, high-quality RCTs are required to further confirm the efficacy of HAIC-oxaliplatin. The present study has been registered with PROSPERO (registration no. CRD42021288497).

Using proton pump inhibitors increases the risk of hepato-biliary-pancreatic cancer. A systematic review and meta-analysis.

Background: More and more studies are focusing on the adverse effects and damage caused by PPI abuse, we carried out a systematic review and meta-analysis for assessing whether the proton pump inhibitor (PPI) leads to hepato-biliary-pancreatic cancer. Methods: PubMed, EMBASE and Web of Science were searched until 1 July 2022, 25 studies (17 case-control and 8 cohort studies; 2741853 individuals) included in this study. Pooled Odd Ratios (ORs) were used for random effect models. Sensitivity analysis and dose-response analysis, subgroup analysis were all conducted. Results: The aggregate OR of the meta-analysis was 1.69 (95% confidence interval (CI): 1.42-2.01, p = 0.01) and heterogeneity (I 2 = 98.9%, p < 0.001) was substantial. According to stratified subgroup analyses, the incidence of hepato-biliary-pancreatic cancer was associated, expect for study design, study quality and region. Risk of hepato-biliary-pancreatic cancer is highest when people is treated with normal doses of PPI. The risks decrease and become insignificant when the cumulative defined daily dose (cDDD) increases. Conclusion: The use of PPI may be associated with an increased risk of hepato-biliary-pancreatic cancer. Hence, caution is needed when using PPIs among patients with a high risk of hepato-biliary-pancreatic cancer.

Safety and efficacy of p38 mitogen-activated protein kinase inhibitors (MAPKIs) in COPD.

Introduction: Chronic inflammation is the core mechanism of the development of chronic obstructive pulmonary disease (COPD). Corticosteroid resistance in COPD limits its anti-inflammatory potency. p38 MAPKIs were suggested as an alternative to corticosteroids despite the fact that there is currently no systematic review evaluating existing evidence. Methods: This randomized controlled trials (RCT)-based systematic review with meta-analysis was conducted following the PRISMA statement. RCTs were searched and screened from 8 databases. Three types of data, including basic information of included studies, pre-defined outcome data, and quality assessment information were extracted. Pooling values and associated 95 % confidence intervals were deemed as statistically significant only when two-tailed p values were smaller than 0.05. Results: This study included 10 RCTs with a total population of 1,751 [age, mean (SD) = 64.39 (8.06)]. Safety and several efficacy indicators of lung function, inflammatory biomarkers, and quality of life were meta-analyzed. Despite the improvement of post-bronchodilator-forced vital capacity (FVC), no difference between p38 MAPKIs and placebo was found in both safety and efficacy. Conclusion: Compared with placebo, p38 MAPKIs are safe but did not show any significant effects in the COPD population. Results of this study should be regarded with caution due to the small number of included studies and heterogeneity from combining different p38 MAPKIs as a whole. Systematic Review registration: PROSPERO #CRD42022302890.

High-Flow Nasal Cannula Oxygen Therapy versus Non-Invasive Ventilation for AECOPD Patients After Extubation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Objective: To evaluate the clinical efficacy of high-flow nasal oxygen therapy (HFNC) and non-invasive ventilation (NIV) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) after extubation. Research Methods: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statements. The primary outcome measures analyzed included: reintubation rate, mortality, complication rate, and ICU length of stay. Results: Eight studies were included, with a total of 612 subjects, including 297 in the HFNC group and 315 in the NIV group. The effect of HFNC and NIV on the reintubation rate of AECOPD patients after extubation, RR (1.49 [95% CI,0.95 to 2.33], P = 0.082). Subgroup analysis with or without hypercapnia according to the included AECOPD population, with hypercapnia, RR (0.69 [95% CI,0.33 to 1.44], P=0.317), without hypercapnia, RR (2.61 [95% CI,1.41 to 4.83], P=0.002). Mortality, RR (0.92 [95% CI,0.56 to 1.52], P = 0.752). ICU length of stay, MD (-0.44 [95% CI,-1.01 to 0.13], P = 0.132). Complication rate, RR (0.22 [95% CI,0.13 to 0.39], P = 0.000). After subgroup analysis, the reintubation rate of HFNC and NIV has no statistical difference in patients with hypercapnia, but NIV can significantly reduce the reintubation rate in patients without hypercapnia. In the outcome measures of complication rate, HFNC significantly reduced complication rate compared with NIV. In mortality and ICU length of stay, analysis results showed that HFNC and NIV were not statistically different. Conclusion: According to the available evidence, the application of HFNC can be used as an alternative treatment for NIV after extubation in AECOPD patients with hypercapnia, but in the patients without hypercapnia, HFNC is less effective than NIV.

Efficacy of Vitamin C Supplementation on Chronic Obstructive Pulmonary Disease (COPD): A Systematic Review and Meta-Analysis.

Background: In recent years, the pleiotropic roles of antioxidants have drawn extensive attention in various diseases. Vitamin C is a well-known antioxidant, and it has been used to treat patients with chronic obstructive pulmonary disease (COPD). This systematic review and meta-analysis aim to demonstrate the impact of vitamin C supplementation in patients with COPD. Methods: We searched PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), SinoMed, Wanfang, and China Science and Technology Journal Database (cqvip.com) for eligible randomized controlled trials (RCTs) from their respective inception to May 18th, 2021, by using the searching terms of COPD, vitamin C, and RCTs. A meta-analysis was performed to evaluate the effects of vitamin C on lung function, antioxidant levels, and nutritional conditions in COPD patients by using Review Manager (Version 5.4). Results: Ten RCTs including 487 participants were eligible for our study. Meta-analysis results showed that vitamin C supplementation (≥400 mg/day) can significantly improve the forced expiratory volume in one second as a percentage (FEV1%) in COPD (SMD:1.08, 95% CI:0.03, 2.12, P=0.04). Moreover, vitamin C supplementation significantly improved the ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) (WMD:0.66, 95% CI: 0.26, 1.06, P=0.001), vitamin C level in serum (SMD:0.63, 95% CI: 0.02, 1.24, P=0.04) and glutathione (GSH) level in serum (SMD:2.47, 95% CI: 1.06, 3.89, P=0.0006). While no statistically significant difference was observed in body mass index (BMI), fat-free mass index (FFMI), vitamin E level and superoxide dismutase (SOD) level in serum. Conclusion: Vitamin C supplementation could increase the levels of antioxidation in serum (vitamin C and GSH) and improve lung function (FEV1% and FEV1/FVC), especially in patients treated with vitamin C supplementation greater than 400 mg/day. However, further prospective studies are needed to explore the role of vitamin C in improving nutritional status.

Elevated expression of the rhythm gene NFIL3 promotes the progression of TNBC by activating NF-κB signaling through suppression of NFKBIA transcription.

BACKGROUND: Epidemiological studies have confirmed that abnormal circadian rhythms are associated with tumorigenesis in breast cancer. However, few studies have investigated the pathological roles of rhythm genes in breast cancer progression. In this study, we aimed to evaluate the aberrant expression of 32 rhythm genes in breast cancer and detect the pathological roles and molecular mechanisms of the altered rhythm gene in regulating the progression of triple negative breast cancer (TNBC). METHODS: The aberrant expression of rhythm genes in breast cancer was screened by searching the GEPIA database and validated by using qRT-PCR and immunohistochemistry staining. Bioinformatics analysis combined with luciferase reporter experiment and chromatinimmunopercitation (ChIP) were used to investigate the molecular mechanism about aberrant expression of identified rhythm gene in breast cancer. The pathological roles of identified rhythm gene in TNBC progression was evaluated by colony formation assay, wound healing experiment, transwell assay, subcutaneous tumor formation and the mouse tail vein injection model through gain-of-function and loss-of-function strategies respectively. mRNA array, bioinformatics analysis, luciferase reporter experiment, ChIP and immunoflurescence assay were employed to investigate the key molecules and signaling pathways by which the identified rhythm gene regulating TNBC progression. RESULTS: We identified that nuclear factor interleukin 3 regulated (NFIL3) expression is significantly altered in TNBC compared with both normal breast tissues and other subtypes of breast cancer. We found that NFIL3 inhibits its own transcription, and thus, downregulated NFIL3 mRNA indicates high expression of NFIL3 protein in breast cancer. We demonstrated that NFIL3 promotes the proliferation and metastasis of TNBC cells in vitro and in vivo, and higher expression of NFIL3 is associated with poor prognosis of patients with TNBC. We further demonstrated that NFIL3 enhances the activity of NF-κB signaling. Mechanistically, we revealed that NFIL3 directly suppresses the transcription of NFKBIA, which blocks the activation of NF-κB and inhibits the progression of TNBC cells in vitro and in vivo. Moreover, we showed that enhancing NF-κB activity by repressing NFKBIA largely mimics the oncogenic effect of NFIL3 in TNBC, and anti-inflammatory strategies targeting NF-κB activity block the oncogenic roles of NFIL3 in TNBC. CONCLUSION: NFIL3 promotes the progression of TNBC by suppressing NFKBIA transcription and then enhancing NF-κB signaling-mediated cancer-associated inflammation. This study may provide a new target for TNBC prevention and therapy.

Structural features determining the vitamin K epoxide reduction activity in the VKOR family of membrane oxidoreductases.

Vitamin K epoxide reductases (VKORs) are a large family of integral membrane enzymes found from bacteria to humans. Human VKOR, specific target of warfarin, has both the epoxide and quinone reductase activity to maintain the vitamin K cycle. Bacterial VKOR homologs, however, are insensitive to warfarin inhibition and are quinone reductases incapable of epoxide reduction. What affords the epoxide reductase activity in human VKOR remains unknown. Here, we show that a representative bacterial VKOR homolog can be converted to an epoxide reductase that is also inhibitable by warfarin. To generate this new activity, we first substituted several regions surrounding the active site of bacterial VKOR by those from human VKOR based on comparison of their crystal structures. Subsequent systematic substitutions narrowed down to merely eight residues, with the addition of a membrane anchor domain, that are responsible for the epoxide reductase activity. Substitutions corresponding to N80 and Y139 in human VKOR provide strong hydrogen bonding interactions to facilitate the epoxide reduction. The rest of six substitutions increase the size and change the shape of the substrate-binding pocket, and the membrane anchor domain stabilizes this pocket while allowing certain flexibility for optimal binding of the epoxide substrate. Overall, our study reveals the structural features of the epoxide reductase activity carried out by a subset of VKOR family in the membrane environment.

Diagnostic value of fractional exhaled nitric oxide in differentiating the asthma-COPD overlap from COPD: a systematic review and meta-analysis.

BACKGROUND: Patients with asthma-COPD overlap (ACO) account for 15-20% of chronic obstructive pulmonary disease (COPD), and the incidence increases with age. Patients with ACO have worse outcomes without proper treatment than those with COPD alone. However, the current diagnostic criteria of ACO are mainly based on symptom features and lack of objective indicators. Recently, several studies have demonstrated that fractional exhaled nitric oxide (FeNO) was higher in ACO than in COPD alone. Thus, this study aims to determine the diagnostic value of FeNO in differentiating ACO from COPD and assisting clinical decision-making. METHODS: We conducted searches in the databases including PubMed, Web of Science, Cochrane Library, and Embase to extract original studies. RESULTS: In all, 10 studies involving 1335 participants were included in this meta-analysis. FeNO level was significantly higher in ACO patients than in patients with COPD alone (WMD = 11.15ppb, 95%CI = 9.01‒13.28; I2 = 18.0%, p = 0.000). The sensitivity and specificity of FeNO in distinguishing ACO from COPD were both 0.71, and the area under the receiver-operating characteristic curve (AUC) was 0.76, indicating that FeNO has moderate diagnostic accuracy in differentiating ACO from COPD. CONCLUSION: FeNO as an inflammatory biomarker is effective in differentiating ACO from COPD and assisting in clinical decision-making.

Monoclonal Antibodies Targeting IL-5 or IL-5Rα in Eosinophilic Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

Background: Although the predominant airway inflammation in chronic obstructive pulmonary disease (COPD) is neutrophilic, approximately 20-40% of COPD patients present with eosinophilic airway inflammation. Compared with non-eosinophilic COPD patients, eosinophilic COPD patients are characterized by a greater number of total exacerbations and higher hospitalization rates. Furthermore, anti-interleukin-5 (IL-5) therapy, consisting of monoclonal antibodies (mAbs) targeting IL-5 or IL-5 receptor α (IL-5Rα), has been proven to be effective in severe eosinophilic asthma. This meta-analysis aimed to determine the efficacy and safety of anti-IL-5 therapy in eosinophilic COPD. Methods: We searched the PubMed, Web of Science, Embase, and Cochrane Library databases from inception to August 2020 (updated in June 2021) to identify studies comparing anti-IL-5 therapy (including mepolizumab, benralizumab, and reslizumab) with placebo in eosinophilic COPD patients. Results: Anti-IL-5 therapy was associated with a decrease in acute exacerbation rate (RR 0.89; 95% CI 0.84 to 0.95, I 2 = 0%) and the severe adverse events (RR 0.90; 95% CI 0.84 to 0.97, I 2 = 0%). However, no significant improvement was observed in pre-bronchodilator forced expiratory volume in 1 s (FEV1) (WMD 0.01; 95% CI -0.01 to 0.03, I 2 = 25.9%), SGRQ score (WMD -1.17; 95% CI -2.05 to -0.29, I 2 = 0%), and hospital admission rate (RR 0.91; 95% CI 0.78 to 1.07, I 2 = 20.8%). Conclusion: Anti-IL-5 therapy significantly reduced the annual acute exacerbation rate and severe adverse events in eosinophilic COPD patients. However, it did not improve lung function, quality of life, and hospitalization rate.

Effect of Omega-3 Fatty Acids on Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

PURPOSE: Omega-3 fatty acid is an emerging hotspot on anti-inflammation and chronic obstructive pulmonary disease (COPD) is known as a chronic inflammatory disease. The effect of Omega-3 fatty acid supplement on patients with COPD remains mixed for insufficient evidence. This systematic review and meta-analysis is based on neat randomized controlled trials trying to give a clearer impression on the effect of Omega-3 on patients with COPD. METHODS: This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statements. Randomized clinical trials (RCTs) published in electronic databases including Medline, Embase, Cochrane Library, ClinicalTrials.gov and China National Knowledge Infrastructure (CNKI) by May 10, 2021 were searched. Data extracted from 6 predetermined domains (nutritional condition, lipid composition, inflammatory biomarker, lung function, physical endurance and quality of life [QoL]) were reviewed and analyzed. RESULTS: A total of 8 RCTs evaluating 418 patients (age, mean [SD] = 67.3 [10.2] years) were included. Statistical differences were found in 3 parameters of 3 domains - weight (Wt) (0.25 [95% CI, 0.02 to 0.48], P = 0.03) in nutritional condition, low-density lipoprotein (LDL) (0.70 [95% CI, 0.30 to 1.10], P = 0.00) in lipid composition and interleukin-6 (IL-6) level (-0.32 [95% CI, -0.60 to -0.05], P = 0.02) in inflammatory biomarker - while no significant difference was found in lung function, physical endurance or QoL. CONCLUSION: Comparing with placebo, Omega-3 intake was associated with more weight-gaining, LDL increase and IL-6 reduction. These results should be interpreted cautiously for the quality and quantity of available evidence are limited.

[An in-gel digestion method of chymotrypsin to improve sequence coverage of membrane protein by mass spectrometry].

In recent years, mass spectrometry has been widely used to study membrane protein structure and function. However, the application of mass spectrometry to study integral membrane protein is limited because there are many hydrophobic amino acids in the trans-membrane domain of integral membrane protein to cause low sequence coverage detected by LC-MS/MS. Therefore, we used vitamin K epoxide reductase (VKORC1), a human integral membrane protein, as a model to optimize the digestion conditions of chymotrypsin, and developed an in-gel digestion method of chymotrypsin to improve sequence coverage of membrane protein by mass spectrometry. By exploring the effects of calcium concentration, pH value and buffer system on the percentage of sequence coverage, number of total detected and types of unique peptide, and the size of unique peptide, sequence coverage and peptide diversity could be considered under condition of Tris-HCl buffer with 5-10 mmol/L calcium ion concentration and pH value 8.0-8.5. This method could make the sequence coverage of membrane protein to reach more than 80%. It could be widely used in the study of membrane protein structure and function, identification of interaction site between membrane proteins, and identification of binding site between membrane protein and small molecular drug.

Characterization of missense mutations in the signal peptide and propeptide of FIX in hemophilia B by a cell-based assay.

Many mutations in the signal peptide and propeptide of factor IX (FIX) cause hemophilia B. A FIX variants database reports 28 unique missense mutations in these regions that lead to FIX deficiency, but the underlying mechanism is known only for the mutations on R43 that interfere with propeptide cleavage. It remains unclear how other mutations result in FIX deficiency and why patients carrying the same mutation have different bleeding tendencies. Here, we modify a cell-based reporter assay to characterize the missense mutations in the signal peptide and propeptide of FIX. The results show that the level of secreted conformation-specific reporter (SCSR), which has a functional γ-carboxyglutamate (Gla) domain of FIX, decreases significantly in most mutations. The decreased SCSR level is consistent with FIX deficiency in hemophilia B patients. Moreover, we find that the decrease in the SCSR level is caused by several distinct mechanisms, including interfering with cotranslational translocation into the endoplasmic reticulum, protein secretion, γ-carboxylation of the Gla domain, and cleavage of the signal peptide or propeptide. Importantly, our results also show that the SCSR levels of most signal peptide and propeptide mutations increase with vitamin K concentration, suggesting that the heterogeneity of bleeding tendencies may be related to vitamin K levels in the body. Thus, oral administration of vitamin K may alleviate the severity of bleeding tendencies in patients with missense mutations in the FIX signal peptide and propeptide regions.

A comparative study of the modulation of the gut microbiota in rats by dietary intervention with different sources of egg-white proteins.

BACKGROUND: Gut microflora dysbiosis has been related closely to a variety of diseases including obesity and inflammatory bowel disease. Proteins and peptides in egg white have been found to alleviate inflammation but the role played by the intestinal flora is still unclear. Using casein as a dietary protein control, we investigated the effects of diets composed of hen egg white, duck egg white, and preserved egg white on gut microbiota in the rat cecum. RESULTS: The gut microbiota in rats were altered after egg-white consumption. The results showed that rats fed with egg white had a similar overall structure of cecal bacterial communities, which was different from those fed with casein. The relative abundance of Akkermansia in the group of rats fed with hen egg white was highest among all groups. Rats fed with duck egg white had significantly higher relative abundance of Proteobacteria and Peptostreptococcaceae, and lower relative abundance of Lachnospiraceae. In addition, the levels of lipopolysaccharide (LPS) and lipopolysaccharide-binding protein (LBP) in rats fed with duck egg white and preserved egg white were lower than the levels in rats fed with hen egg white. CONCLUSION: Our results indicated the possible positive effect on homeostasis of the intestinal flora brought about by the intake of duck egg white. This study provides an insight into the potential positive impact of preserved egg white on health by changing gut microbiota and affecting the antigen load. © 2020 Society of Chemical Industry.

Sagittaria sagittifolia polysaccharide protects against isoniazid- and rifampicin-induced hepatic injury via activation of nuclear factor E2-related factor 2 signaling in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The Sagittaria sagittifolia L. polysaccharide (SSP) is a purified form of a homogeneous polysaccharide isolated from the root tubers of S. sagittifolia, which has been used as a protectant against hepatotoxicity induced by coadministration of isoniazid and rifampicin. However, the protective effect of SSP against isoniazid- and rifampicin-induced liver injury has never been studied. AIM OF THE STUDY: In this study, the hepatoprotective effect of SSP and its underlying mechanism were investigated in mice with isoniazid- and rifampicin-induced liver injury. MATERIALS AND METHODS: Liver injury was induced in mice by intragastric administration of isoniazid and rifampicin, and the mice were divided into the following six groups: standard control (administration of saline by gavage), model (intragastric administration of isoniazid and rifampicin at 100 mg/kg/day each), positive control (100 mg/kg/day silymarin by gavage 4 h after isoniazid and rifampicin administration), and SSP-treated (200, 400, or 800 mg/kg/day SSP by gavage after isoniazid and rifampicin administration). Subsequently, blood and liver samples were collected from all the animals and were assessed. RESULTS: SSP significantly alleviated the liver injury, as evidenced by decreased activities of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in the serum and a decreased level of malondialdehyde in the liver, as well as by an increased level of glutathione and increased activities of superoxide dismutase and catalase in the liver. SSP also effectively reduced the pathological tissue damage. The gene and protein expression of cytochrome P450 (CYP) 2E1 and CYP3A4 was inhibited by SSP. The gene and protein expression of nuclear factor erythroid 2-related factor 2 (NRF2), glutamate-cysteine ligase, and heme oxygenase-1 were induced by SSP, whereas that of Kelch-like ECH-associated protein 1 was inhibited. CONCLUSIONS: SSP exerts a protective effect against isoniazid- and rifampicin-induced liver injury in mice. The underlying mechanisms may involve activation of NRF2 and its target antioxidant enzymes and inhibition of the expression of CYPs.